Contextual learning plays an important role in triggering drug craving and relapse, two core features of drug addiction. It is thought that alteration in synaptic plasticity in the reward circuit underlies drug-associated learning. As such, blocking drug-induced alteration of synaptic plasticity will provide a novel therapeutic strategy for treating drug addiction. The ventral tegmental area (VTA) of the midbrain is a key component of the reward circuit that mediates the addictive properties of many drugs of abuse, including cocaine. Our recent work has shown that in VTA dopamine neurons long-term potentiation (LTP) of glutamatergic excitatory transmission is tightly controlled by 3-aminobutyric acid (GABAergic) inhibition and repeated cocaine exposure in vivo facilitates LTP induction by reducing GABAergic inhibition. Understanding its underlying mechanisms is instrumental in finding ways to block this reduced GABAergic inhibition. We hypothesize that repeated cocaine exposure in vivo induces a long-term depression-like modulation of inhibitory transmission (I-LTD) of VTA dopamine neurons, which underlies cocaine-induced reduction of GABAergic inhibition, facilitation of LTP induction and development of addictive behavior. By combining electrophysiological recordings with behavioral tests, we will test this hypothesis via three Specific Aims. Aim I will identify conditions and mechanisms for I- LTD induction in dopamine neurons of midbrain slices; Aims II and III will determine whether in vivo application of inhibitors of this I-LTD induction blocks the cocaine-induced reduction of GABAergic inhibition, facilitation of LTP induction and addictive behavior. Drugs that increase GABA level in the brain have been used in clinical trials as a potential pharmacotherapy for cocaine dependence, suggesting that manipulation of GABAergic inhibition is in principle a sound therapeutic strategy for treating cocaine addiction. However, universal increase in GABAergic inhibition throughout the brain produces side effects. Selective blockade of cocaine-induced reduction of GABAergic inhibition, an objective of this proposal, could help develop anti-addiction treatments that would be more efficacious than global enhancement of GABAergic inhibition. PUBLIC HEALTH RELEVANCE This project investigates the mechanisms for cocaine addiction and seeks to develop novel therapeutic strategy for treating cocaine addiction.